1. Field of the Invention
This invention relates to compositions, especially animal feeds, for treating coccidiosis in animals, such compositions containing an osmoprotectant, and especially, betaine, with or without coccidiostat. The compositions of the invention are also useful for the treatment of clinical or subclinical coccidiosis symptoms, including such symptoms that arise after vaccination against the disease.
2. Background of the Invention
Loses due to parasitic diseases are among the chief causes of economic loss to the livestock and poultry industry. The availability of antiparasitic treatments has enabled the development of higher levels of livestock and poultry production. Efficient and economic antiparasitic treatments also facilitate a worldwide supply of relatively cheap protein. Effective parasite prevention and control is especially important in the poultry industry, where the positive economic impact of antiparasitic prophylaxis, treatment and therapy is significant.
Coccidiosis is a common disease in domestic food animals, caused by protozoa belonging to the Eimeria family. Coccidiosis is found worldwide, and its economical impact, particularly on poultry farming, is huge. In the U.S. poultry industry alone, coccidiosis causes losses of 200-250 million dollars yearly. World-wide, coccidiosis is estimated to cause one third of all disease and mortality losses in the poultry industry (Trends in Veterinary Research and Development, part 6, Anti-coccidials, Lloyd-Evans, L. P. M. (ed.), PJB Publications Ltd., 1991).
Animals harboring coccidiosis infections may manifest severe or mild clinical symptoms or they may be entirely subclinical. The site of infection, i.e., tissue tropism, depends on the species of the parasite and the host. The majority of Eimeria and Isospora species infect the animal's intestinal epithelium. Severe infections are characterized by diarrhea, dehydration, emaciation and death. Mild and subclinical infections may manifest no overt clinical symptoms, but nevertheless the animals may suffer depressed growth, impaired feed conversion, loss of skin pigmentation and downgrading of the animal's assessed quality in terms of fitness for human consumption.
In chickens, typical clinical signs of coccidiosis include ill-thrift (lack of thriving), rapid loss of weight, diarrhea, and dysentery. The most serious effects take place in the intestine, where coccidia invade the mucosae and cause epithelial damage, lesions and hemorrhage. Physiologically, coccidiosis causes severe disturbances in the acid-base, ionic and osmotic balance of the gut, and decreases nutrient absorption (Ruff, Georgia Coccidiosis Conference, Nov. 19-21 (1986) pp. 169-183; Gwyther et al., Coccidia and Intestinal Coccidiomorphs, Vth International Conf., Oct. 17-20 (1989) pp. 279-284).
Since the 1950s, several dietary drugs (coccidiostats) have been developed to treat coccidiosis, but with only moderate success. The most serious drawbacks associated with the use of coccidiostats have been: 1) rapidly developing resistance of the parasites; 2) adverse effects on host animals; and 3) risk for residuals or quality defects in the consumer products. While the universal use of coccidiostats has decreased serious mortality outbreaks, subclinical effects of coccidiosis on animals markedly decrease productivity (Jeng & Edgar, Highlights of Agricultural Research--Alabama, Agricultural Experiment Station, v.28, p. 6 (1981)). Therefore, compositions and methods for decreasing the use of coccidiostats or increasing their efficacy are needed.
Many coccidiostats in common use kill parasites by breaking down their ionic and osmotic regulation. However, these drugs are not coccidia specific; they also alter the ionic and osmotic balance of the host and, consequently, may decrease nutrient absorption in the gut (Speight, 6th European Symposium on Poultry Nutrition, World's Poultry Science Assoc., Oct. 11-15 (1987), abstract 7A). As a result, the positive effect of coccidiostats on mortality may be offset by their detrimental side effects with regard to nutrient availability, growth and feed efficiency. Methods for protecting the animals against the detrimental side effects of the ionophoric coccidiostats are also needed.
Vaccination of animals has become an alternative, if not the preferred method for the treatment and prevention of parasitic diseases in animals. However, vaccination is not free of side effects. The most serious drawback of the vaccines, is that they tend to reduce the growth and feed efficiency of the animals, because the vaccine deliberately induces mild symptoms of the disease in the animal. This effect may last for a few weeks after the vaccine has been introduced. These side-effects negatively impact on the vaccinated animal's performance and thus also have an adverse economic impact.
Vaccines, especially, attenuated live vaccines are useful in the poultry industry for the inoculation of birds against coccidiosis. Live vaccines are also used, but are mostly limited to breeder flocks. Live vaccines are not considered suitable for broiler production because of the potential accumulation of live parasites in the litter.
In the use of vaccines against Eimeria parasites in poultry, the use of attenuated live anticoccidial vaccines has been limited to layers (egg-laying hens) and broilers that are grown to heavier weights. The use of these vaccines has been limited to chickens with longer growing periods because only these chickens have sufficient time to recover from the ill side-effects of the vaccine and thus are able to compensate for the vaccine-induced loss in growth. Therefore, methods for eliminating the side-effects of vaccination with coccidiosis vaccines are needed.
Betaine is an osmoprotectant. It increases the osmotic strength of cells without adversely affecting enzyme activity, and it protects enzymes from ionic or temperature inactivation (Nash et al., Aust. J. Plant Physiol. 9:47-57 (1982); Yancey et al., Science 224:1064-1069 (1982); Rudolph et al., Archives Biochem. Biophys. 245:134-143 (1986); McCue & Hanson, Trends in Biotechnology 8:358-362 (1990); Papageorgiou et al., Curr. Res. In Photosynthesis 1:957-960 (1990)). While some organisms (and tissues) can accumulate betaine in high quantities under osmotic stress through osmotically induced betaine synthesis, most animals lack this capability, and are dependent upon the intake of exogenous betaine. For example, isolated salmon liver mitochondria, when exposed to osmotic stress, show increased betaine intake, but not synthesis (Bjorkoy, G., Synthesis and Accumulation of glycine betaine in Salmon (Salmo salar) and a Mussel, MSc thesis, Norwegian College of Fisheries, University of Tromso, pp. 94).
Betaine has mainly been studied for its ability to act as a methyl donor in transmethylation reactions (Stekol et al., J. Biol. Chem. 203:763-773 (1953)) and for its ability to transfer methyl groups to homocysteine to produce methionine Harper, H. A., in: Review of Physiological Chemistry, Appleton & Lange, Publ., Los Altos, Calif., pp. 120 and 351 (1973)). Although betaine's chemical osmoprotective properties were known prior to the present invention, it was not appreciated that betaine or other osmoprotectants might be useful, in vivo, in alleviating the undesirable side effects associated with coccidiosis infection. In addition, it was not previously recognized that osmoprotectants, and especially betaine, plus a coccidiostat can act favorably together, even synergistically, to improve the commercial performance of domestic food animals suffering from coccidiosis.